OCD is a severe, heritable condition with a lifetime prevalence of about two percent of world populations. The mode of inheritance is incompletely understood but is likely complex, involving multiple genetic loci of small to moderate effect. Our laboratory has played a leading role in studies of OCD and of its genetics for over 25 years, and was one of the founding sites of multi-center genome-wide studies of OCD, partial results of which have recently been reported in the group's publications noted below. In addition, a series of association studies that has identified and evaluated candidate genes in OCD and related disorders is continuing. In our Lab's continuing and collaborative investigations, we have worked to clarify the fundamental phenotypical features of OCD and related disorders, sometimes designated 'OCD spectrum disorders', in two reports published in 2011. We are currently left with a multifaceted array of obsessive-compulsive features that cut across traditional diagnostic designations (DSM-IV) as well as draft plans for the DSM-5. In continuing efforts, our group and our collaborators have been using latent class modeling to go beyond factor and cluster analyses in order to parse OCD and related disorders into more valid groups. Considering underlying features, stressors and the other environmental events will provide additional elements to evaluate in these investigations. Examples of some sub-disorders that can contribute to OCD but can be found without classic OCD features include our recent and prior studies of hoarding and dystonias as well as of comorbid affective disorders, including bipolar disorder. The latter disorder is also under direct genetic study in continuing collaborative investigations. Studies of the role of serotonin, SLC6A4 and other major serotonin genes in OCD and related disorders are ongoing. The strong relationship of SLC6A4 variants to different SRI treatment responses in humans represents an additional illustration of gene-based influences on serotonergic pharmacologic responses, i.e., a new SERT-based pharmacogenomics, directly relevant to the treatment of human neuropsychiatric disorders such as OCD and depression as well as to other serotonin-related human diseases. Recent evidence from treatment studies and genetic studies suggest that another neurotransmitter system may contribute to OCD. As with SERT in the serotonin system, the neuronal glutamate transporter is a major regulator of glutamate availability. This glutamate transporter is encoded by the gene SLC1A1 located within the chromosomal region 9p24. Recent evidence from 9p24 gene linkage analyses and candidate gene studies have suggested possible involvement of SLC1A1 in the development of OCD. Our large case-control study of SLC1A1 included over 950 OCD probands and controls collected by our Lab. In addition, SLC1A1 expression and genotype data were evaluated to gain further insights into SLC1A1 function. We found that gene expression of SLC1A1 is heritable in human cell lines. We identified three SNPs in or near SLC1A1 that correlated with gene expression levels. Additionally, two of these SNPs also predicted expression levels in human post-mortem brain tissue, and one SNP was found to have functional consequences in reporter gene studies. We are currently continuing further lab-based studies of this gene using transgenic techniques in mice. Our case-control data corroborated previous smaller, family-based studies. A recent large, comprehensive collaborative family-based investigation of 1576 individuals identified additional SLC1A1 associated with OCD. These investigations, taken together, indicate that SLC1A1, like SLC6A4, is a susceptibility gene for OCD. The expression and database-mining approach that we used provides a new and useful complementary model approach to strengthen future candidate gene studies in neuropsychiatric and other disorders which represent a large public health burden. In fact, seven neuropsychiatric disorders, including OCD, were listed in the 2001 World Health Organizations report on the leading causes of years of extended disability among adults. In additional studies of the genetics of OCD, we focused on candidate genes for OCD based on animal models of some OCD-related compulsive behaviors. For example, mice deficient in the postsynaptic synapse-associated protein Sapap3 develop an OCD-like phenotype, including compulsive grooming and increased anxiety-like behaviors. We resequenced SAPAP3 in DNA samples from OCD patients and from others with related disorders in a case-control study, investigating the complete coding region and flanking intronic sequences of SAPAP3. Importantly, we detected seven novel non-synonymous variants. These SAPAP3 variants were present in 4.2% of diagnosed OCD and related disorder patients, but only in 1.1% of controls. Thus, we observed a meaningful case-control association in our moderately-sized sample with the majority of changes being missense mutations, while one variant was an in-frame insertion of five amino acids. It is thus possible that a combination of relatively rare susceptibility variants may prove contributory to OCD, as suggested for some other disorders including autism as well as for OCD itself in our prior ongoing studies of the SLC6A4 uncommon variant, Ileu425Val. Our data is thus in support of the multiple rare variant/common disease hypothesis versus the common variant/common disease hypothesis currently debated in the scientific literature. The combination of the Sapap3 mouse model with compulsive behaviors and our recent, first case-control study of the SAPAP3 gene in humans with OCD demonstrates a role for SAPAP3 in OCD and compulsive behaviors. In fact, a follow-up study recently reported from our collaborative study of siblings who were both affected by OCD found that four of six SNPs investigated in SAPAP3 were nominally associated with grooming disorders such as compulsive hair-pulling, with high genotypic relative risks of 1.6-3.3. These studies thus bring an even sharper focus on OCD subtypes or sub-populations that may be more closely related to specific single genes. In continuing studies based on this model, we are currently pursuing the first studies in humans, of the neuronal cadherin gene, CDH2, originally identified from an investigation of canine compulsive behaviors. Also of note is that our group continues to share our 25+ year collection of DNA and phenotype data with collaborators in the Obsessive-Compulsive Disorder Collaborative Genetics Study (OCGS) and the Obsessive-Compulsive Foundation (OCF) groups, as well as with other intramural and extramural individual collaborators, thus enhancing the global search for underlying contributions to OCD and related disorders that are of major public health concerns. Multiple papers that were published in the last year that are listed below resulted from these collaborative studies.